Forced Expiratory Flow at 25-75% as a Marker for Airway Hyper Responsiveness in Adult Patients with Asthma-like Symptoms.

Background
The aim of the present study was threefold: to assess the association between baseline FEF25-75 and Airway Hyper-responsiveness (AHR), to specify whether a decrease in FEF25-75 may reflect severe hyper-responsiveness, and finally to confirm a FEF 25-75 cut-off value.


Materials and Methods
In a cross sectional study in Imam Khomeini Hospital, Ahvaz, patients suffering from respiratory symptoms due the 2013 autumn rainfall with normal FEV1 and FEV1/FVC were evaluated by methacholine challenge test. Those with PD20<1000, 10002000 μg were classified as severe, moderate and mild AHR, respectively. Data were analyzed using Chi-square, Independent t-test, One-way ANOVA and Receiver Operating Characteristic (ROC) curve.


Results
Among the 234 patients, mean baseline FEF25-75 was 84.2±22.7% for 54 patients having a negative bronchial provocation test result and 70.9±19.2% for 179 patients with a positive bronchial provocation test result (P < 0.0001). No change was observed in the median PD20 among patients with a higher baseline FEF25-75. ROC analysis showed that FEF25-75 could potentially be a predictor of AHR, but it could not confirm the cut-off value of FEF25-75 for these patients.


Conclusion
When asthma begins, AHR could be predicted by impaired FEF25-75 with normal FEV1 and FEV1/FVC. However, we could not determine a cut-off value, and no association was found between a greater impairment of FEF25-75 and a more severe AHR.


INTRODUCTION
Bronchial hyper-responsiveness is defined as an abnormal bronchial response to stimulants and it has been considered as a typical characteristic of chronic asthma (1).
One of the most important parameters for the diagnosis and post-diagnosis follow-up of asthma is the Forced Expiratory Volume in 1 second (FEV1). However, recent studies have demonstrated that asthmatic patients with a normal FEV1 may have ventilatory defects (2) and suggest another parameter which is the expiratory flow between 25% and 75% of vital capacity (FEF25-75) which is more reflective of small airways and a sensitive indicator of symptomatic asthma, compared to FEV1, in detecting airways limitation (2)(3)(4). What distinguishes FEF25-75 from FEV1 is the fact that the recorded values in the latter are concerned with the whole bronchial tree, while the former TANAFFOS provides values specifically related to the bronchial zone between division 7 and division 19, the internal diameter of which is between 0.5 and 2 mm. In addition, whereas the values of FEV1 are more reliable in showing the degree of bronchial obstruction, FEF25-75 is more variable and sometimes used when FEV1 is within normal limits (5,6).
Since small airways are more susceptible to inflammatory and remodeling processes, it is important to determine whether FEF25-75 is a preferred tool in assessing AHR when the methacholine challenge test is performed (7,8). The combination of a low FEF25-75 and a normal FEV1 as a hallmark of asthma is not yet well established (4). No guidelines have been offered as to find normal FEF25-75 values. In this regard, a FEF25-75 cut-off value has recently been proposed for a group of asthmatic children: FEF25-75 less than 65% of predicted is considered impaired (3). The Methacholine Challenge Test (MCT) has been used universally to assess bronchial hyper-responsiveness in patients with asthma. Although MCT is as a standard method to confirm the presence of airway hyperresponsiveness, it has its own limitations (in available and cost of procedure) that restrict its use as a tool for definitive diagnosis of asthma (10). Consecutive methacholine doses are administered until FEV1 is seen to decrease by 20 percent (PD20) (11).
The current study was designed to assess the presence of Airway Hyper-responsiveness (AHR) in a large group of adults suffering from an acute rainfall dyspnoea, to examine the relationship between FEF25-75 and methacholine airway responsiveness, to confirm a cut-off value for FEF25-75 in these patients and determine a relationship between baseline FEF25-75 and AHR. More specifically, the relationship between a greater impairment of FEF25-75 and a more severe AHR was aimed to be investigated.

Patients and Study Design
The present study was a cross-sectional study carried In addition, no change in the median PD20 was observed among patients whose baseline FEF25-75% was higher. In order to determine optimal discrimination threshold values for FEF25-75, ROC curve was used, but a cut-off point for bronchial hyper-responsive could not be determined ( Figure 2).

DISCUSSION
The present study, carried out on patients with asthma like symptoms and normal pulmonary function, highlights that a drop in baseline FEF25-75 is associated with a rise in the number of hyper responsive patients but does not correspond with levels of AHR. Furthermore, we can only say that a smaller rate of FEF25-75 denotes an AHR risk factor.
We did not find a major FEF25-75 cut-off value to distinguish hyper-reactive from normo-reactive subjects. The study limitation was the absence of long term follow up of patients for evaluating and comparing the number of asthma exacerbations and patients' outcome.
In conclusion, patients with asthma symptoms and "normal" FEV1, FVC and FEV1/FVC, but impaired FEF25-75, are recommended to perform a bronchoprovocation test. Unfortunately, a significant cut-off of FEF25-75 could not be found to help find the distinction between hyper-reactive and normo-reactive airway in that FEF25-75 can be low in normo-reactive subjects. In addition, no association was found between a greater impairment of FEF25-75 and a more severe AHR.